Summary Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that affects 5 million people worldwide. Frequently, SLE affects the central and peripheral nervous system, a syndrome collectively named neuropsychiatric SLE (NPSLE). Cognitive dysfunction (CD) is a significant problem in NPSLE that is reported to affect a broad range of patients, reflecting the complexity of the disease, the lack of standard criteria for diagnostics, and the need for additional research. Accumulating evidence demonstrates the involvement of Toll-like receptors (TLRs) in SLE, and IRAK4 is a key kinase that initiates signaling by most TLRs involved in SLE. By studying the role of IRAK4 in SLE prone mice we found a link between lupus and brain microvascular endothelial cells, and importantly, detected specific chemokines that are also associated with CD. We hypothesize that inhibition of IRAK4 activity will alleviate NPSLE by reducing CD. This will be tested by identifying the cellular and molecular brain alterations in a lupus mouse model in which the IRAK4 activity is abolished that include, profiling brain and serum chemokines and also activation states and signaling pathways in brain tissue using cutting-edge Imaging Mass Spectrometry analysis. Lastly, we will test if abolishing IRAK4 activity impacts CD using the same model. These findings will advance our understanding of IRAK4 signaling in NPSLE, facilitate design of drugs to attenuate CD, and pave the way for translational studies in NPSLE patients.